UNAIDS estimates that 14,000 persons are newly infected with HIV every day throughout the world, of which one half are between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV-1 transmission, and the protection afforded by condom use. Novel concepts for HIV-1 prevention are urgently needed. We propose to evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in a randomized and blinded trial of daily oral tenofovir 300 mg versus placebo among men in Peru, who have extremely high risk of acquiring HIV infection. Daily oral tenofovir 300 mg is selected for evaluation because it is FDA-licensed for human use, allows once a-day dosing, is well-tolerated, is active against many drug resistant HIV-1 strains, and was demonstrated to be effective for prevention in non-human primate models. We propose to enroll 2100 men who will be randomized 1:1 to receive daily oral tenofovir 300 mg versus placebo and followed for 13 months for HIV-1 seroconversion (aim 1), adverse events (aim 2), and viral load, drug resistance and CD4 T cell count after seroconversion (aim 3). Study sites are selected in Peru because of their well-developed prevention research infrastructure and their demonstrated ability to recruit men at high risk for HIV infection with outstanding rates of retention. Recruitment will be derived from 3 cities in Peru that had the highest incidence of HIV-1 infection in two recent surveys, have the required infrastructure to support a closely monitored clinical trial, and represent enormous genetic and geophysical diversity. The sample size is sufficient to detect cost-effective levels of HIV-1 prevention. The trial also aims to evaluate the safety of this agent in HIV uninfected persons, including the incidence of mild renal insufficiency and liver inflammation. Chemoprophylaxis may involve durable benefits or risks as well, possibly leading to an attenuated course of infection due to early inhibition of viral replication or drug resistance. The proposed research addresses important gaps of knowledge directly, including the safety and efficacy of daily oral tenofovir chemoprophylaxis among men exposed to HIV after rectal exposure. This unique and essential information bears directly on HIV prevention in the Americas and will not be available after the completion of other studies planned for the United States, Asia and Africa. The safety and efficacy of chemoprophylaxis may differ in men and women due to differences in reproductive biology, the mucosal surfaces that are typically exposed to HIV, behavioral differences, and pharmacokinetics. This research ultimately aims to break the epidemic cycle of HIV-1 by protecting men at risk for HIV, and may spare their sexual partners and their future children.